Metabolic Substrate Utilization During c-Myc Induced Cardiac Hypertrophy

描述(由申请者提供)：在这个为期5年的培训计划中描述的主要目标是在学术儿科心脏病学方面的职业发展。首席研究员已完成临床培训，并有两年时间专注于基于实验室的研究。这项建议将通过研究代谢底物利用变化在代偿性心肌肥厚的发展和维持中的作用来扩展主要研究人员的科学技能。该计划包括发起人、心脏新陈代谢专家迈克尔·波特曼博士。大卫·霍根贝里博士，联合导师和顾问，将以他在细胞生长和分裂的生物能调节方面的丰富知识为该项目提供帮助。共同导师查尔斯·默里博士(LJW)是心肌细胞发育和再生方面的专家，将为肥厚的评估提供指导。正在提出一项培训计划，包括具体的课程、会议和成立一个咨询委员会，以指导他成长为一名成功的独立调查员。C-Myc(Myc)调节肥大，维持心功能。然而，其机制大多尚不清楚。肿瘤学文献确定了特定的Myc基因网络，包括碳水化合物代谢。由于已知代谢和肥厚之间的联系，我们将研究代谢网络。我们假设：MYC信号向碳水化合物利用的代谢转变，这种转变介导了代偿性肥厚的发展和维持。我们的目标包括：1)确定在Myc诱导的小鼠肥厚发展之前是否存在向增加碳水化合物利用的代谢转变，2)确定抑制Myc诱导的底物转移是否损害这些小鼠代偿性肥厚的发展和/或维持，3)确定Myc是否是压力超负荷反应中心肌碳水化合物代谢增加的主要介质，4)确定Myc诱导的长期主动脉结扎小鼠是否可以通过改变心脏底物利用来保护代偿性肥厚。儿童医院致力于基础科学研究和内科科学家的培养。华盛顿大学有一个充满活力的心血管研究社区，可以根据需要提供技术专业知识。这些机构的资源组合将为首席研究员提供充足的机会，成功地发展成为一名学院化的儿科心脏病专家。相关性(参见说明)：心力衰竭在成年人中的年死亡率约为10%，因此，研究人员不断尝试寻找新的治疗方法来改善患者的预后。原癌基因Myc调节代偿性肥大。对Myc诱导的肥厚有益方面的机械理解为开发成人和儿童心力衰竭的新疗法提供了可能性。(摘要结束)

DESCRIPTION (provided by applicant): The primary goal described in this 5 year training program is the development of a career in academic Pediatric Cardiology. The principal investigator has completed clinical training w/ith two additional years focused on laboratory- based research. This proposal will extend the principal investigator's scientific skills through investigation into the role of metabolic substrate utilization changes in the development and maintenance of compensated cardiac hypertrophy. This plan includes the sponsor, Dr. Michael Portman, an expert on cardiac metabolism. Dr. David Hockenbery, co- mentor and consultant, will assist the project with his extensive knowledge on bioenergenic regulation of cell growth and division. Co-mentor Dr. Charles Murry (LJW) is an expert on cardiomyocyte development and regeneration will provide mentorship in evaluation of hypertrophy. A training plan is presenting including specific coursework, conferences and the formation of an Advisory Committee lo guide his development into a successful independent investigator. C-Myc (Myc) regulates hypertrophy and maintains cardiac function. However, the mechanisms are mostly unknown. The oncology literature identifies specific Myc gene networks including carbohydrate metabolism. Due to known links between metabolism and hypertrophy, we will investigate the metabolic network. We hypothesize that: Myc signals a metabolic shift towards carbohydrate utilization and that this shift mediates the development and maintenance of compensated hypertrophy. Our aims include: 1) Determine if a metabolic shift towards increased carbohydrate utilization temporally precedes the development of hypertrophy in Myc-induced mice, 2)Determine if inhibiting the Myc- induced substrate shift impairs the development and/or maintenance of compensated hypertrophy in these mice, 3)Determine whether Myc is a major mediator of increased myocardial carbohydrate metabolism in the response to pressure overload, 4) Determine if Myc induction in long-term aortic banded mice can preserve compensated hypertrophy through changes in cardiac substrate utilization. Children's Hospital has a strong commitment to basic science research and the development of physician-scientists. The University of Washington has a vibrant cardiovascular research community which can provide technical expertise as needed. The combined resources of these institutions will provide ample opportunity for the principal investigator to successfully develop into an academic pediatric cardiologist. RELEVANCE (See instructions): Heart failure has an annual mortality rate of around 10% in adults, therefore, researchers are constantly trying to identify new therapies to improve patient outcomes. The protooncogene Myc regulates compensated hypertrophy. A mechanistic understanding of the beneficial aspects of Myc-induced hypertrophy offers the potential for developing novel therapies for heart failure in adults and children. (End of Abstract)